tbuckley/cabot-search huggingface dataset:
Abstract 6011: RNA-seq analysis of liver from NASH derived HCC model mouse treated with streptozotocin-high fat diet
Authors: Taishi Hashiguchi, Bui Phuong Linh, Yuki Sakakibara, Ryuto Tanaka, Elizabeth H Pigney
Journal: Cancer Research (2022)

Abstract Introduction; Non-alcoholic steatohepatitis (NASH) is a chronic liver disease often associated with type 2 diabetes. It sometimes progresses to more serious conditions such as liver fibrosis and hepatocellular carcinoma (HCC). Therapeutic agents for NASH have not yet been developed, and an animal model with high clinical correlation is required. The STAM mouse is a NASH model mouse with a background of type 2 diabetes. This mouse model shows the same pathological progression as human NASH patients, and has been used for the evaluation of many drug candidates, as well as basic research. However the gene profile, including mutations, has not been elucidated in this model. In this study, we analyzed the RNA-seq data of STAM mice at each pathological stage and examined the clinical correlation at the gene level. Methods;NASH was induced in male mice by a single subcutaneous injection of 200 ug streptozotocin solution 2 days after birth and feeding with high fat diet after 4 weeks of age. The mice were sacrificed and livers collected at 6, 8, 10, 12, 16 and 20 weeks of age. For liver samples, the left lateral lobe was snap frozen in liquid nitrogen and stored at -80°C for RNA-seq analysis. Total RNA of the cells was isolated using RNeasy mini kit. Results: The gene expression of the canonical pathway in NASH progression from steatosis to hepatocellular carcinoma was analyzed. Increased expression was observed in CCL2, TLR4, HSP47, alpha-SMA, c-Myc, and cyclin D1. Since it has been reported that genetic traits are involved in the development of NASH-HCC, we next analyzed the genetic mutations in the STAM mice. The number of individuals showing mutations in Mtorinvolved in Insulin signaling increases as the disease progresses, especially in the liver cancer phase. Citation Format: Taishi Hashiguchi, Bui Phuong Linh, Yuki Sakakibara, Ryuto Tanaka, Elizabeth H Pigney. RNA-seq analysis of liver from NASH derived HCC model mouse treated with streptozotocin-high fat diet [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6011.
Acrylamide fragment inhibitors that induce unprecedented conformational distortions in enterovirus 71 3C and SARS-CoV-2 main protease
Authors: Bo Qin, Gregory B. Craven, Pengjiao Hou, Julian Chesti, Xinran Lu, Emma S. Child, Rhodri M.L. Morgan, Wenchao Niu, Lina Zhao, Alan Armstrong, David J. Mann, Sheng Cui
Journal: Acta Pharmaceutica Sinica B (2022)

RNA viruses are critically dependent upon virally encoded proteases to cleave the viral polyproteins into functional proteins. Many of these proteases exhibit a similar fold and contain an essential catalytic cysteine, offering the opportunity to inhibit these enzymes with electrophilic small molecules. Here we describe the successful application of quantitative irreversible tethering (qIT) to identify acrylamide fragments that target the active site cysteine of the 3C protease (3Cpro) of Enterovirus 71, the causative agent of hand, foot and mouth disease in humans, altering the substrate binding region. Further, we re-purpose these hits towards the main protease (Mpro) of SARS-CoV-2 which shares the 3C-like fold and a similar active site. The hit fragments covalently link to the catalytic cysteine of Mpro to inhibit its activity. We demonstrate that targeting the active site cysteine of Mpro can have profound allosteric effects, distorting secondary structures to disrupt the active dimeric unit.
Abstract LB002: Development of fully human anti-CD19 &amp;CD22 bispecific tandem CAR-T for the treatment of resistant or relapsed B cell malignancies
Authors: Jenna Nguyen, Gening Zhang, Keming Zhang, Ning Jiang, Ryan Feng, Jeffrey Wong, Annie Luu, Yan Chen, Kehao Zhao
Journal: Cancer Research (2022)

Abstract Background: CD19 CAR-T has revolutionized the cancer immunotherapy for B cell malignancies. However, 40-50% patients have relapsed post current CD19 monospecific CAR-T treatment within 24 months. It has been shown that the resistance mechanism relates to either lack of persistency of the CAR-T in patients or due to CD19 target escape during treatment. CD19 and CD22 are co-expressed on B cells during B cell maturation and on most B cell malignancies. We have developed a fully human anti-CD19 and CD22 bispecific tandem CAR, aiming to overcome CD19 target escape mechanism and be more persistent with improved production process. Methods: Utilizing mRNADis࣪ mRNA display and live cell selections, we have discovered a set of human anti-CD19 and anti-CD22 scFvs with a broad affinity range and broad epitope coverage. We have generated EPC-001, an optimal CD19/CD22 bispecific tandem CAR-T candidate, by precise engineering of multiple pairs of CD19/CD22 tandem scFvs with monospecific and bispecific target binding properties, linker length and scFv orientation. Results: EPC-001 demonstrated both mono-specific and bivalent CD19 and CD22 target cell engagement, which led to CAR-T cell mediated cytotoxic cancer cell killing, cytokine release and CAR-T proliferation. EPC-001 showed improved Tscm and Tcm early phenotype and demonstrated potent anti-tumor activity in Raji-luciferase disseminated animal model, as well as persistent CAR-T activity when mice re-challenged with additional tumor cells. Furthermore, we have developed CD19 and CD22 knockout Raji animal models and demonstrated the in vivo mechanism of EPC-001 in overcoming CD19 or CD22 target escape resistance mechanism. Conclusion: EPC-001 is a promising candidate that potentially prevents target escape by bivalent targeting of CD19 and CD22 simultaneously and overcome target escape with mono-specific engagement and CAR activation. EPC-001 has been advanced into clinic for proof of concept in investigator-initiated trial to treat CD19 CAR-T resistant/relapsed patients. Citation Format: Jenna Nguyen, Gening Zhang, Keming Zhang, Ning Jiang, Ryan Feng, Jeffrey Wong, Annie Luu, Yan Chen, Kehao Zhao. Development of fully human anti-CD19 &amp;CD22 bispecific tandem CAR-T for the treatment of resistant or relapsed B cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB002.
Abstract 832: Breast cancer plasticity is restricted by a LATS1-NCOR1 repressive function
Authors: Yael Aylon, Noa Furth, Giuseppe Mallel, Nishanth Nataraj, Gilgi Friedlander, Ori Hassan, Rawan Zoabi, Benjamin Cohen, Tomer Salame, Saptaparna Mukherjee, Randy Johnson, Efrat Shema, Moshe Oren
Journal: Cancer Research (2022)

Abstract Purpose of study: Understanding the epigenetic mechanism underlying luminal-to-basal plasticity of breast cancer subtypes Experimental procedures: Epigenetic focused CyTOF, ATAC-seq, RNA-seq, FACS-sorting, Proximity Ligation Assay, orthotopic syngeneic injections of tumor cells to mouse mammary gland, and others. Summary: Breast cancer is the most frequent cancer in women. It is defined by specific types of tumors that are classified into distinct histological and molecular subtypes. However, lately, with the advent of single-cell technologies, the extent of cellular and functional intratumoral heterogeneity within breast cancer subtypes is being appreciated. Much of this heterogeneity, including transitions of luminal-to-basal cell identity, can be attributed to alterations in the activity of chromatin remodelers. The transcriptional corepressor, NCOR1, and the tumor suppressor, LATS1, are downregulated in luminal breast cancer tumors with poor prognosis. Here, we show that LATS1 impedes the emergence of an epigenetically distinct basal-like population in luminal B tumors by augmenting NCOR1 repressive activity and facilitating deacetylation of H3K27ac. Conclusion: Rigorous repression of ERα-repressed genes facilitated by LATS1-NCOR1 maintains luminal cell identity and restricts progression of luminal breast cancer. Citation Format: Yael Aylon, Noa Furth, Giuseppe Mallel, Nishanth Nataraj, Gilgi Friedlander, Ori Hassan, Rawan Zoabi, Benjamin Cohen, Tomer Salame, Saptaparna Mukherjee, Randy Johnson, Efrat Shema, Moshe Oren. Breast cancer plasticity is restricted by a LATS1-NCOR1 repressive function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 832.
Abstract 1916: Using systems medicine for comprehensive metabolic profiling of tumors: how tumor metabolism shapes prognosis and response to chemotherapy
Authors: Daniel Cook, John A. Cole, Patricia Carrigan, Joseph R. Peterson
Journal: Cancer Research (2022)

Abstract Background: Metabolic disfunction is one of the hallmarks of cancer, and metabolism-based therapies are a key class of chemotherapeutics. Despite this, there has previously been no systematic way to identify metabolism-based targets for therapeutic intervention. This is especially concerning when considering that targeting tumor metabolism has been shown to increase the efficacy of standard chemotherapy in pre-clinical studies. We therefore developed a systems medicine approach to interrogate tumor metabolism systematically, identify the effects of metabolic heterogeneity on overall survival prognosis, and gain insights into new metabolism-associated targets or therapies to complement standard of care for cancer patients. Method: Our systems medicine framework statistically integrates metabolic network modeling with RNA-sequencing data (RNA-seq). This allows us to integrate molecular data about individual tumors (from RNA-seq) with a curated knowledge base of how these molecules interact within a patient’s tumor (using metabolic network models). This results in a mathematical description, or model, of a specific tumor’s metabolism that is able to be interrogated (i.e., it is high-dimensional like RNA-seq data) and able to be simulated (i.e., we can “drug” the model and investigate downstream effects). Results: We applied this systems medicine approach across a range of tumor types, including lung adenocarcinoma, pancreatic adenocarcinoma, metastatic melanoma, clear cell renal cell carcinoma, and salivary cystic adenoid carcinoma. Within each cancer type, we found significant patient-to-patient metabolic heterogeneity. Across cancer types, a consistent pattern that emerged was that the metabolic systems with the most patient-to-patient heterogeneity were also the systems most associated with patient overall survival. This result suggests that metabolic variability is a key driver of tumor response to therapy and overall patient survival. Furthermore, targeting metabolic pathways in a patient-specific manner could enhance chemotherapy in tumors with metabolic profiles associated with poor prognosis. Conclusion: This study shows that the specific metabolic profiles of tumors are key drivers of overall survival. We therefore believe that metabolic tumor characterization and intervention could be a useful strategy to enhance chemotherapy efficacy and overall survival in patients across tumor types. Citation Format: Daniel Cook, John A. Cole, Patricia Carrigan, Joseph R. Peterson, The SimBiosys Team. Using systems medicine for comprehensive metabolic profiling of tumors: how tumor metabolism shapes prognosis and response to chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1916.
Abstract 6169: Identification of molecules mediating natural killer cell-pancreatic stellate cell interactions
Authors: Zoe X. Malchiodi, Allison Fitzgerald, Elena Galvano, Louis M. Weiner
Journal: Cancer Research (2022)

Abstract Pancreatic stellate cells (PSCs) are the main sources of cancer-associated fibroblasts in pancreatic ductal adenocarcinoma (PDAC), which account for at least 50% of PDAC’s total tumor volume and its dense desmoplastic stroma. In recent years, immune-stromal cell interactions have been the subject of research in a variety of diseases. Interestingly, natural killer (NK) cells are relatively understudied in PDAC and may be exploited to identify new treatment opportunities. We have explored how NK cell-PSC interactions are mediated by known NK cell ligands. Human PSC (hPSC, CRC-811) or PDAC (MIA-PaCa-2, PANC-1) cell lines were co-cultured with DiO stained NK cells (NK-92, donor NK cells) for 4 hours, then target cells were assessed for apoptosis by flow cytometry using AnnexinV and Sytox stains. We found that although NK cells lyse both PSCs and PDAC cells, there was more NK cell-mediated lysis against PSCs. Using flow cytometry, we found that PSCs express the well-known MICA/B ligand, which binds the activating NKG2D receptor on NK cells to initiate its cytotoxic activity. In co-culture, neutralizing MICA/B in vitro did not completely inhibit NK cell-mediated lysis of PSCs, suggesting other interactions need to be explored. To identify other molecular determinants, NK cell ligand and receptor expression was evaluated by quantitative PCR in human PSC, PDAC, NK, and other leukocytic (K562) cell lines. Cell surface validation of highly expressed NK cell ligands and receptors were confirmed by flow cytometry and/or Western blot. NK cell ligands that were both highly expressed and localized to the cell surface were: NKG2D ligands—MICA and ULBP2 (both activating), KIR2DS4 (CD158I) ligand—HLA-A (activating), and NKp44 ligands—NKp44L and PCNA (activating and inhibitory, respectively). Their corresponding receptors were also expressed and localized to the cell surface by NK cells. These results highlight novel NK cell-PSC interactions that may mediate immune suppression in PDAC. These findings warrant further investigation. Citation Format: Zoe X. Malchiodi, Allison Fitzgerald, Elena Galvano, Louis M. Weiner. Identification of molecules mediating natural killer cell-pancreatic stellate cell interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6169.
Abstract 2306: BLU-222, an investigational, potent, and selective CDK2 inhibitor, demonstrated robust antitumor activity in <i>CCNE1</i>-amplified ovarian cancer models
Authors: Victoria Brown, Phil Ramsden, Nealia House, Richard Vargas, Jian Guo, Ruduan Wang, Riadh Lobbardi, Maxine Chen, Douglas Wilson, Joseph Kim, Neil Bifulco, Michelle Maynard, Emanuele Perola, Dean Zhang, Steve Wenglowsky, Yoon Jong Choi
Journal: Cancer Research (2022)

Abstract Background: Cyclin-dependent kinases (CDK) are a class of enzymes that, along with their regulatory cyclin binding partners, drive cell cycle progression. Cell cycle dysregulation is a hallmark of cancer and targeting its genetic drivers can confer therapeutic benefits. Cyclin E1 (CCNE1) gene alterations are common in patients with ovarian cancer and can be found in ~20% of high-grade serous ovarian cancer cases, which tend to be platinum therapy resistant and therefore represent a high medical need. Cyclin E1 is the canonical binding partner of CDK2, which becomes constitutively active when CCNE1 is amplified and overexpressed. Selectively inhibiting CDK2 is an attractive therapeutic option for CCNE1-amplified tumors and may limit off-target CDK-driven toxicities. Here we report preclinical validation studies leading to the development of an orally available CDK2 inhibitor, BLU-222, for the treatment of ovarian cancer harboring a CCNE1 amplification. Methods: BLU-222 selectivity was measured by enzyme assays, cellular target engagement assays (NanoBRET), and proliferation assays in a panel of ovarian cancer cell lines. In vitro cellular potency was assessed by phospho-Rb levels. In vivo antitumor activity of BLU-222 as a single agent or in combination with carboplatin was measured in an OVCAR-3 cell line-derived xenograft (CDX) tumor model harboring a CCNE1 amplification. Results: BLU-222 demonstrated selectivity, both biochemically and in cells, with low nanomolar potency for CDK2 vs other CDK family members (CDK1, -4, -6, -7, and -9). In a panel of ovarian cancer cell lines, those with CCNE1 amplifications were highly sensitive to BLU-222. Consistent with the in vitro profiling, BLU-222 exhibited significant antitumor activity in the OVCAR-3 CDX model. While administration of single-agent carboplatin led to stasis in vivo, the combination of BLU-222 + carboplatin induced durable tumor regression even after treatment cessation. Conclusions: These data provide a strong rationale for advancing BLU-222 towards clinical development in patients with CCNE1-amplified ovarian cancer. Citation Format: Victoria Brown, Phil Ramsden, Nealia House, Richard Vargas, Jian Guo, Ruduan Wang, Riadh Lobbardi, Maxine Chen, Douglas Wilson, Joseph Kim, Neil Bifulco, Michelle Maynard, Emanuele Perola, Dean Zhang, Steve Wenglowsky, Yoon Jong Choi. BLU-222, an investigational, potent, and selective CDK2 inhibitor, demonstrated robust antitumor activity in CCNE1-amplified ovarian cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2306.
Abstract 3031: Impact of pyruvate kinase isoforms on cysteine metabolism in pancreatic cancer
Authors: Elliot Ensink, Sophia Y. Lunt
Journal: Cancer Research (2022)

Abstract Pancreatic cancer cells undergo metabolic alterations to survive within a nutrient-depleted tumor microenvironment. Cysteine metabolism in particular is critical for supporting pancreatic cancer cell survival through its role in redox homeostasis. Targeting cysteine metabolism presents an underexplored opportunity for therapeutic exploitation, but much remains unknown about how cysteine metabolism is influenced by microenvironmental conditions and the overall metabolic state of the cell. One critical metabolic shift in pancreatic cancer cells occurs through altered isoform expression of the glycolytic enzyme, pyruvate kinase (PKM). Pancreatic cancer cells preferentially switch from the constitutively active M1 isoform to the allosterically regulated M2 isoform of PKM. Overexpression of PKM2 in pancreatic cancer cells produces a profound reprogramming of many metabolic pathways; however, the precise relationship between PKM isoform expression and cysteine metabolism is not well understood. We hypothesize that PKM isoform selection enables pancreatic cancer cell survival within a low cystine tumor microenvironment by reprogramming metabolic activity to increase cystine import and glutathione production and modulate glucose and glutamine metabolism to resist oxidative stress. We used lentiviral CRISPR-Cas9 vectors to genetically modify two human pancreatic ductal adenocarcinoma cell lines, AsPC-1 and Panc-1, to exclusively express either PKM1 or PKM2. We evaluated the effects of PKM isoform selection on tolerance of low cystine environments by assessing viability under a range of cystine concentrations (0 – 50 μM) reflective of physiologic and cystine starvation conditions. We observe altered viability and proliferation in PKM1 vs. PKM2 expressing cells under normoxic (21%) and hypoxic (1% O2) conditions. Targeted metabolomics using stable isotope labeling tracers further reveal impacts of PKM isoform expression in central carbon metabolism when cystine is limited. Additional experiments to elucidate the precise mechanism by which PKM isoform expression impacts pancreatic cancer cells are currently under investigation. This study provides valuable insight into the complexities of metabolic reprogramming within the tumor microenvironment and enhances our understanding of how cysteine metabolism could be targeted for the treatment of pancreatic cancer. Citation Format: Elliot Ensink, Sophia Y. Lunt. Impact of pyruvate kinase isoforms on cysteine metabolism in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3031.
Abstract 3078: A pipeline for functional precision medicine in bone and soft tissue sarcoma organoids
Authors: Ahmad Al Shihabi, Peyton J. Tebon, Jomjit Chantharasamee, Huyen T. Nguyen, Sara Sartini, Ardalan Davarifar, Nasrin Tavanaie, Scott D. Nelson, Noah Federman, Jane Yanagawa, Alice Soragni
Journal: Cancer Research (2022)

Abstract Bone and soft tissue sarcomas span a spectrum of over one hundred histologic subtypes. Developing clinical trials and identifying effective therapies remains a challenge given the rarity of these tumors and scarcity of available tumor models. Patient-derived tumor organoids (PDTOs) are representative of the native physiology of tumors across an array of malignancies (Phan et al, 2019; Al Shihabi et al, 2021). For rare tumors such as bone and soft tissue sarcomas, PDTOs could constitute an important tool to better understand the biology of the disease and identify treatment options. Here, we present the pipeline we have established at UCLA to systematically procure tissue, develop and characterize individualized sarcoma PDTOs, and identify tumor sensitivities using high-throughput drug screening. We have collected tumor specimens from 114 patients diagnosed with sarcomas, representing more than 30 distinct subtypes of soft tissue and bone tumors. We have established suitable conditions to generate organoids from over 100 samples collected from needle biopsies, tumor resections, and metastasectomies, including soft tissue sarcomas (liposarcoma, undifferentiated pleomorphic sarcoma, leiomyosarcoma, etc.) and bone sarcomas (chondrosarcoma, osteosarcoma, Ewing sarcoma, etc.). We take advantage of our mini-ring technology to generate PDTOs in a format compatible with high-throughput drug screening (Phan et al, 2019; Nguyen et al, 2020). Our results highlight tumor-specific drug susceptibilities to chemotherapeutics, targeted agents, and combination therapies, generating results within a week from surgery. We will show how several of the organoid response patterns we identified transcend cancer subtype and patient characteristics. Our findings support the feasibility of rapidly generating individualized organoid models from bone and soft tissue sarcomas to facilitate biological interrogations and investigate response to treatment. Direct testing of PDTOs derived from clinical specimens can provide timely, actionable information for functional precision medicine approaches with the potential to improve patient outcomes. Citation Format: Ahmad Al Shihabi, Peyton J. Tebon, Jomjit Chantharasamee, Huyen T. Nguyen, Sara Sartini, Ardalan Davarifar, Nasrin Tavanaie, Scott D. Nelson, Noah Federman, Jane Yanagawa, Alice Soragni. A pipeline for functional precision medicine in bone and soft tissue sarcoma organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3078.